Progress in the Fight Against Multidrug-Resistant Bacteria 2005-2016: Modern Noninferiority Trial Designs Enable Antibiotic Development in Advance of Epidemic Bacterial Resistance

Abstract

From a public health perspective, new antibacterial agents should be evaluated and approved for use before widespread resistance to existing agents emerges. However, for multidrug-resistant pathogens, demonstration of superior efficacy of a new agent over a current standard-of-care agent is routinely feasible only when epidemic spread of these dangerous organisms has already occurred. One solution to enable proactive drug development is to evaluate new antibiotics with improved in vitro activity against MDR pathogens using recently updated guidelines for active control, noninferiority trials of selected severe infections caused by more susceptible pathogens. Such trials are feasible because they enroll patients with infections due to pathogens with a "usual drug resistance" phenotype that will be responsive to widely registered standard-of-care comparator antibiotics. Such anticipatory drug development has constructively reshaped the antibiotic pipeline and offers the best chance of making safe and efficacious antibiotics available to the public ahead of epidemic resistance.

Keywords: antibacterial drug development; antimicrobial drug resistance; bacterial resistance; noninferiority trial design.

Figure 1.

Initial antibacterial approvals by route and indication, 1995–2016. Initial approvals of antibacterial agents from 1995 to 2016 were retrieved from CDERWatch and Drugs@FDA and are shown by approved route and number of initially approved indications (some agents were approved for >1 indication). As needed due to evolution of indication terminology, indications were grouped. The 2016 approval of bezlotoxumab to reduce recurrence of Clostridium difficile infection is not shown. Abbreviations: CABP, community-acquired bacterial pneumonia; cIAI, complicated intra-abdominal infection; cSSTI, complicated skin and skin structure infection; cUTI, complicated urinary tract infection; Genital, uncomplicated gonorrhea, prostatitis, nongonococcal urethritis, and chlamydia; IV, intravenous; Meningitis, bacterial meningitis; NP, nosocomial pneumonia including hospital- and ventilator-associated pneumonia; Mild RTI, acute otitis media, acute bacterial exacerbation of chronic bronchitis, acute sinusitis, and pharyngitis/tonsillitis; uSSTI, uncomplicated skin and skin structure infection; uUTI, uncomplicated urinary tract infection.